Oxidation hypothesis has generated an overwhelming interest in how it might affect the atherogenic process. Despite the plethora of pro-atherogenic effects of oxidative stress, several major problems plague the hypothesis. These include, cellular defense to oxidative stress, prooxidant nature of exercise, PUFA, and estrogens, and the rapid clearance of oxidized LDL from plasma. There is an a priori need to amend the hypothesis to include these factors. Based on findings in literature and our preliminary results, we propose that "oxidative stress in plasma might result in an elevated tissue (arterial) antioxidant enzyme induction and, in addition, such oxidative stress might itself could lead to lower plasma cholesterol levels." In other words, an oxidative stress might help to maintain a high level of antioxidant protection in tissues and combined with the lowering of plasma cholesterol, would help to attenuate the atherogenic process. We propose the following specific aims: 1. To demonstrate that oxidative stress would lead to elevated tissue antioxidant defense and decrease atherosclerosis. 2. To demonstrate that oxidative stress might lead to decreased LDL cholesterol levels via an enhanced clearance of oxidized lipoproteins or via decreased de novo liver cholesterol synthesis mediated by cholesterol oxidation products. 3. To demonstrate that antioxidant supplementation during the "beneficial oxidative stress acclimatization period" would be counter productive and reduce the beneficial effects of plasma oxidative stress. 4. To determine the effects of exercise-induced oxidative stress on the regression of atherosclerotic lesions in LDL r -/- mice. Since fatty streak lesion starts early in life, the study would suggest that the consumption of PUFA rich diet and exercise from childhood would ensure adequate antioxidant defense and protection from atherosclerosis. Exercise is also recommended for other diseases such as diabetes and hypertension, diseases in which oxidative stress is also implicated. Thus the outcome of this study will have far reaching implications.